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KR-20260066052-A - Crystalline form of bezuclatinib, method of preparation thereof, and use thereof

KR20260066052AKR 20260066052 AKR20260066052 AKR 20260066052AKR-20260066052-A

Abstract

The present invention relates to a crystalline form of bazuclatinib and a method for preparing the same, a pharmaceutical composition comprising said crystalline form, and the use of said crystalline form in the preparation of a drug for inhibiting the KIT D816V mutation and a drug for treating gastrointestinal stromal tumors and progressive systemic mastocytosis.

Inventors

  • 장, 위싱
  • 첸, 지아러
  • 멍, 리핑

Assignees

  • 코젠트 바이오사이언시스, 인크.

Dates

Publication Date
20260512
Application Date
20240715
Priority Date
20230728

Claims (15)

  1. Compound I A crystalline form of Compound I, wherein the X-ray powder diffraction pattern by Cu-Kα radiation has characteristic peaks at 2θ at 7.5°±0.2°, 13.7°±0.2°, and 16.8°±0.2°.
  2. The crystalline form of claim 1, wherein the X-ray powder diffraction pattern by Cu-Kα radiation has a characteristic peak at at least one of 2θ among 13.0°±0.2°, 15.1°±0.2°, and 18.9°±0.2°.
  3. In paragraph 2, the crystalline form having an X-ray powder diffraction pattern by Cu-Kα radiation with a characteristic peak at at least one of 2θ among 22.8°±0.2°, 23.6°±0.2°, and 25.6°±0.2°.
  4. In claim 1, the X-ray powder diffraction pattern by Cu-Kα radiation is substantially crystalline, as shown in FIG. 1.
  5. Compound I A crystalline form of Compound I, wherein the X-ray powder diffraction pattern by Cu-Kα radiation has characteristic peaks at 2θ at 8.6°±0.2°, 12.5°±0.2°, and 22.0°±0.2°.
  6. In claim 5, the crystalline form of compound I, wherein the X-ray powder diffraction pattern by Cu-Kα radiation has a characteristic peak at at least one of 2θ among 7.9°±0.2°, 10.9°±0.2°, and 26.1°±0.2°.
  7. In claim 5, the crystalline form of compound I, wherein the X-ray powder diffraction pattern by Cu-Kα radiation has a characteristic peak at at least one of 2θ, between 18.1°±0.2° and 28.8°±0.2°.
  8. In paragraph 5, the X-ray powder diffraction pattern by Cu-Kα radiation is substantially the crystalline form of compound I as shown in FIG. 7.
  9. Compound I A crystalline form of Compound I, wherein the X-ray powder diffraction pattern by Cu-Kα radiation has characteristic peaks at 2θ at 7.4°±0.2°, 11.5°±0.2°, and 16.2°±0.2°.
  10. In claim 9, the crystalline form of compound I, wherein the X-ray powder diffraction pattern by Cu-Kα radiation has a characteristic peak at at least one of 2θ among 13.4°±0.2°, 14.9°±0.2°, and 18.0°±0.2°.
  11. In claim 9, the crystalline form of compound I, wherein the X-ray powder diffraction pattern by Cu-Kα radiation has a characteristic peak at 2θ of 13.7 ±0.2°.
  12. In claim 1, the X-ray powder diffraction pattern by Cu-Kα radiation is substantially the crystalline form of compound I as shown in FIG. 12.
  13. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form and pharmaceutically acceptable excipient of any one of claims 1, 5 and 9.
  14. Use of the crystalline form according to any one of claims 1, 5 and 9 in the manufacture of a drug for inhibiting the KIT D816V mutation.
  15. Use of the crystalline form according to any one of claims 1, 5 and 9 in the manufacture of drugs for the treatment of gastrointestinal stromal tumors and progressive systemic mastocytosis.

Description

Crystalline form of bezuclatinib, method of preparation thereof, and use thereof The present invention relates to the field of crystal chemistry, and in particular to the crystalline form of bezuclastinib, the method of preparing the same, and the use of the same. Bezuclatinib is an oral selective tyrosine kinase receptor inhibitor (TKI) developed by Cogent Biosciences. Bezuclatinib can inhibit the KIT D816V mutation and is used to treat gastrointestinal stromal tumors (GIST) and advanced systemic mastocytosis (AdvSM) with positive clinical outcomes. The chemical name of bezuclatinib is 3,4-dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide (hereinafter referred to as 'Compound I'), and its structural formula is as follows: WO2014100620A3 and WO2021222442A1 disclose a method for synthesizing Compound I, but do not disclose the crystalline form of Compound I. A crystal is a solid in which molecules of a compound are arranged in a three-dimensional order within a microstructure to form a crystal lattice. Polymorphism refers to the phenomenon in which a compound takes on a polycrystalline form. While a compound may exist in one or more crystalline forms, their existence and properties cannot be specifically predicted. Different crystalline forms of active pharmaceutical ingredients (APIs) possess different physical and chemical properties; this leads to different dissolution and absorption of the drug in vivo, which can subsequently affect the drug's clinical efficacy to some extent. In particular, for some insoluble oral solid or semi-solid formulations, the crystalline form is critical to product performance. Furthermore, the physical and chemical properties of the crystalline form are critical to the production process. Therefore, polymorphism is an important aspect of drug research and drug quality control. In order to develop drugs containing Compound I, a new crystalline form is required to meet medical needs. The inventors of this application have unexpectedly discovered a crystalline form of Compound I provided by the present invention that is advantageous for at least one of solubility, hygroscopicity, purification effect, stability, adhesion, compressibility, fluidity, in vitro and in vivo solubility, and biological efficacy. In particular, it has good stability, low hygroscopicity, and is suitable for use in medicine, which is of great significance for the development of drugs containing Compound I. The present invention provides a crystalline solid of compound I, a method for preparing the same, and a pharmaceutical composition comprising said crystalline solid. According to the object of the present invention, the present invention provides a crystalline solid of compound I. According to the object of the present invention, the present invention provides a crystalline form of compound I, CSI (hereinafter referred to as 'crystalline form CSI'). In one embodiment, the X-ray powder diffraction pattern of crystalline CSI by Cu-Kα radiation has characteristic peaks at 1, 2, or 3 diffraction angles 2θ of 7.5°±0.2°, 13.7°±0.2°, and 16.8°±0.2°. Preferably, the X-ray powder diffraction pattern of crystalline CSI has characteristic peaks at diffraction angles 2θ of 7.5°±0.2°, 13.7°±0.2°, and 16.8°±0.2°. In addition, the X-ray powder diffraction pattern of crystalline CSI by Cu-Kα radiation has characteristic peaks at one, two, or three diffraction angles 2θ of 13.0°±0.2°, 15.1°±0.2°, and 18.9°±0.2°; preferably, the X-ray powder diffraction pattern of crystalline CSI has characteristic peaks at diffraction angles 2θ of 13.0°±0.2°, 15.1°±0.2°, and 18.9°±0.2°. In addition, the X-ray powder diffraction pattern of crystalline CSI by Cu-Kα radiation has characteristic peaks at one, two, or three diffraction angles 2θ of 22.8°±0.2°, 23.6°±0.2°, and 25.6°±0.2°; preferably, the X-ray powder diffraction pattern of crystalline CSI has characteristic peaks at diffraction angles 2θ of 22.8°±0.2°, 23.6°±0.2°, and 25.6°±0.2°. In another embodiment, the X-ray powder diffraction pattern of crystalline CSI by Cu-Kα radiation has characteristic peaks at 1, 2, 3, 4, 5, 6, 7, 8, or 9 of the diffraction angles 2θ at 7.5°±0.2°, 13.7°±0.2°, 14.7°±0.2°, 16.8°±0.2°, 13.0°±0.2°, 15.1°±0.2°, 18.9°±0.2°, 22.8°±0.2°, 23.6°±0.2°, and 25.6°±0.2°. Without limitation, the X-ray powder diffraction pattern of crystalline CSI by Cu-Kα radiation is substantially as shown in Fig. 1. Without limitation, the thermogravimetric analysis diagram of crystalline CSI is substantially as shown in FIG. 2 and has a mass loss of about 0.01% when heated to 100 °C. Without limitation, crystalline CSI is infinite. According to the object of the present invention, the present invention provides a crystalline form of compound I, CSII (hereinafter referred to as 'crystalline form CSII'). In one embodiment, the X-ray powder diffraction pattern of crystalline CSII by Cu-Kα radiation has characteristic peaks at one, two, or three diffracti